This invention relates to the treatment of skin conditions, comprising those conditions requiring stimulation of melanocyte proliferation and to the inhibition of melanomas. The invention is of especial application to the treatment of vitiligo and skin cancer.
Vitiligo is a common skin pigment disorder characterised by the development of patchy de-pigmented lesions. Current treatments which include the use of photosensitisers (eg psoralens) with UVA radiation (PUVA), corticosteroids or skin grafting have low success rates and are generally accompanied by unpleasant side effects. Vitiligo has a highly detrimental impact on the emotional well-being of the sufferer, the disfiguring effects of the disease being compounded by the absence of a suitable treatment. Although vitiligo patches are not believed to contain melanocytes (pigment producing cells), a reservoir exists in hair follicles in vitiliginous skin. Thus activation of hair follicular melanocytes is a crucial process in the repigmentation of vitiliginous skin.
Certain plant remedies, usually administered as mixtures of herbs or extracts, particularly those used in traditional Chinese medicine and Indian Ayurvedic medicine, have been employed for the treatment of vitiligo for a long time and in many cases have given positive results in small scale studies. Herbs such as Psoralea corylifolia L. and Vernonia anthelmintica Willd. (=Centratherum anthelminticum Kuntze) are well known for their use in this disease. Psoralens, which are employed in the modern PUVA and khellin in KUVA therapy were originally derived from plant sources (Psoralea corylifolia L and Ammi visnaga respectively) used in traditional remedies for vitiligo. However these therapies rely on the use of UV irradiation for their efficacy, which is associated with the aetiology of skin cancer.
The fruit of black pepper (Piper nigrum L.) and long pepper (Piper longum L.) are both important medicinal herbs in Ayurvedic and Unani (traditional Indian) medicine systems, in which remedies generally consist of mixtures of herbs. A wide range of the medicinal uses of black pepper have been documented by Kirtikar and Basu (Indiam Medicinal Plants, 2nd Edition, Vol. 3, (1935) pages 2128-2135), including its use in the treatment of leucoderma. Black pepper has also been implicated as a possible adjunct to Vernonia anthelmintica in the treatment of leucoderma (Indian Medicinal Journal, Vol. 1, 3rd Edition, (1982) 1267-1270). These two herbs are employed as a constituent in many traditional herbal preparations for a variety of uses, including gastrointestinal and skin ailments. Compositions comprising black pepper, ginger and pipali have been used in the treatment of vitiligo (Ancient Science of Life, Vol. IX, No. 4 (1990) 202-206); however, the specific therapeutic action of black pepper in this orally administered composition has not been established.
There is, therefore, a need for further compounds and compositions, which are able to stimulate the proliferation of melanocytes.
It has been surprisingly found that, piperine, which is present in the fruit of Piper nigrum, stimulates the replication of melanocytes. The action of piperine is to increase the number of cells which confer pigmentation. Piperine is the compound (E,E)-1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine and should not be confused with piperidine.
Piperine has also been reported to occur in other Piper species ie. P. acutisleginum, album, argyrophylum, attenuatum, aurantiacum, betle, callosum, chaba, cubeba, guineense, hancei, khasiana, longum, macropodum, nepalense, novae hollandiae, peepuloides, retrofractum, sylvaticum. Pharmaceutical compositions containing piperine have been used in the treatment of tuberculosis and leprosy (EP 0 650 728). It has also been suggested that piperine is able to enhance the bioavailability of the other constituents of a pharmaceutical composition (WO 96/25939).
The invention provides a method of treating a subject (human or animal) having a skin condition requiring stimulation of melanocyte proliferation and melanomas, which comprises administering to the subject, preferably to the site of the condition, an effective amount of piperine or an active analogue or derivative thereof, as hereinafter defined.
The active ingredient may be used on its own, but is more suitably used in combination with a carrier or excipient and optionally one or more further active ingredients. It may also be used in the form of an isolate or plant extract, in the case of piperine itself derivable from Piper nigrum, for example.
Stimulation of melanocyte proliferation greatly facilitates the re-pigmentation of de-pigmented skin, e.g. post traumatised de-pigmented skin. The term xe2x80x9cpost traumatised de-pigmented skinxe2x80x9d means the skin formed during the healing process that occurs after a skin trauma. De-pigmentation may arise, for example, from scar tissue formed as a result of a skin trauma such as burn or other skin lesion or may be due to vitiligo. The present invention can be used to treat any of these skin disorders in a patient.
Generally in this invention, the piperine or active derivative or analogue thereof may be administered by oral, topical, intravenous or subcutaneous (intra-muscular) routes but is preferably applied topically (to the area of the skin where treatment is desired).
The active ingredient may be formulated as a solid powder; a paste, ointment or cream; a tablet or capsules; or a solution.
The method of the invention may also be used to treat a person having a skin condition which would benefit from coloration, e.g. to enhance or promote the natural colouring of the skin. The treatment may be used for prophylactic, therapeutic or cosmetic purposes.
Piperine and its analogues or derivatives as hereinafter defined inhibit the proliferation of melanoma cells. Thus, they may also be used in the treatment of skin cancer. Another aspect of the invention therefore provides a method of treating skin cancer in a human or animal patient comprising the administration to said patient of a therapeutically effective amount of piperine or an active analogue or derivative thereof, as hereinafter defined.
The piperine or active analogue or derivative thereof may be administered by oral or topical routes. Suitable dosage forms may be any of those discussed above.
The formula of piperine and derivatives and analogues thereof usable in this invention is given below. 
wherein
n=0 or 1;
p is 0 or 1;
q is 0 or 1
when n=p=q=0, R3 and R4 represent hydrogen or together represent a carbon to carbon double bond;
when n=0 and one of p and q=1, R3 and R4 together and one of R5 and R6 together or R7 and R8 together represent carbon to carbon double bonds, R3 and R4 together represent a carbon to carbon double bond and R5 and R6 or R7 and R8 represent hydrogen atoms, R3 and R4 represent hydrogen and one of R5 and R6 together or R7 and R8 together represent carbon to carbon double bonds or R3, R4, R5, R6, R7 and R8 all represent hydrogen atoms;
when n=0 and p=q=1, R3 and R4 together and one of R5 and R6 together or R7 and R8 together represent carbon to carbon double bonds the other of R5, R6, R7 and R8 representing hydrogen, R3 and R4 together represent a carbon to carbon double bond and R5 and R6 or R7 and R8 represent hydrogen atoms, R3 and R4 represent hydrogen and one of R5 and R6 together or R7 and R8 together represent carbon to carbon double bonds the other of R5, R6, R7 and R8 representing hydrogen, R3 and R4 together, R5 and R6 together and R7 and R8 together represent carbon to carbon double bonds or R3, R4, R5, R6, R7 and R8 all represent hydrogen atoms;
or optionally when n is 1 R2 and R3 together represent a carbon to carbon double bond and one or more of R4 and R5 together, R5 and R6 together, R6 and R7 together or R7 and R8 together represent a carbon to carbon double bond the other of R4 to R8 representing hydrogen;
m=1, 2 or 3;
when m=1, R1 represents an alkoxy group having from 1 to 3 carbon atoms or a hydroxy group;
when m=2, each R1 independently represents an alkoxy group having from 1 to 3 carbon atoms or the two R1s together represent a 3xe2x80x2,4xe2x80x2-methylenedioxy group;
when m=3, two R1s together represent a 3xe2x80x2,4xe2x80x2-methylenedioxy group and the other R1 represents an alkoxy group having from 1 to 3 carbon atoms or a hydroxy group;
R9 represents a pyrrolidino, piperidino, 4-methylpiperidino or morpholino group, a N-monoalkylamino group of 4 to 6 carbon atoms, a N-monocycloalkylamino group of 4 to 7 carbon atoms, a 3xe2x80x2,4xe2x80x2-methylenedioxy-substituted benzylamino or 2-phenethylamino group or R9 represents an alkoxy group of 1 to 6 carbon atoms;
in any of its E, Z geometrically isomeric forms.
Certain of the active analogues or derivatives of piperine of formula (1) are new. The present invention therefore includes such compounds, and pharmaceutical compositions containing them together with a carrier or excipient.